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© 2002 American Society for Clinical Oncology
Substitute "Prostate Cancer" for "Neuroblastoma"?AFLAC Cancer Center, Emory University/Children’s Healthcare of Atlanta, Atlanta, GA NEUROBLASTOMA, the most common solid tumor affecting children younger than 5 years of age, affects 650 children yearly in the United States; approximately one in 7,000 will develop the cancer within the first 5 years of life.1 This incidence is twice that of phenylketonuria, nine times that of galactosemia, and slightly less than neonatal hypothyroidism, all commonly screened infant diseases in North America.2 Children diagnosed before the age of 1 year, representing 40% of all cases, have an extremely favorable prognosis, even when presenting with metastatic disease.3 This circumstance has led to consideration of screening infants for early detection of the disease, using specific catecholamine markers, which are easily detected in urine.2 The theory that pediatricians could lower mortality by preclinical detection of neuroblastoma has been very appealing. In pioneering work, Japanese investigators in Kyoto and Sapporo City demonstrated that neuroblastoma could be detected by screening for urinary catecholamines at 6 months of age, with evidence of improvement in neuroblastoma survival.4,5 However, several methodologic limitations in these and other Japanese studies have precluded definitive conclusions. None of the early studies used population-based approaches for neuroblastoma screening.4,5 Subsequent studies, which were conducted in relatively small populations, found no diminution in late-stage, poor-biology disease.6-9 Furthermore, only retrospective control groups were used in all of these studies. Once quantitative methods for measuring catecholamine metabolites were implemented, there was a strong suggestion of an increase in neuroblastoma incidence in Japan.10 This would artificially elevate survival, without affecting total deaths. Because of these facts, Japanese investigators have been limited to retrospective analyses of the potential benefit of neuroblastoma screening. In this issue of the Journal of Clinical Oncology, in the best study from Japan to date, Yamamoto et al11 compare neuroblastoma-screened infants to retrospective controls, as well as to the unscreened subgroup within the screening cohort. They demonstrate that screening 6-month-olds markedly increases the incidence of the disease. No significant decrease in the incidence of neuroblastoma was found for children older than 1 year, who are at high risk for unfavorable outcomes. A nonsignificant decrease in mortality was observed when screened children were compared with various controls. Some of the mortality difference between the screened cohort and retrospective controls can assuredly be related to changes in therapy over 20 years. But even mortality between the nonrandomized screened and unscreened subgroups during the most recent era studied (children born in the late 1980s to early 1990s) revealed no significant differences (P = .73). The authors conclude, "Usefulness of 6-month screening as a public health service is questionable," and "decrease in mortality. . . would be slight and should be balanced against the adverse effect of overdiagnosis, the cost of screening, and the psychological burden on children and families."11 During the early phases of Japanese neuroblastoma screening efforts, there was a loud clamor to implement screening in North America and Europe. Instead, several consortia received funding to study the efficacy of screening for neuroblastoma in infants to determine whether such an approach actually resulted in lower cancer-related mortality. The two largest of these studies were the Quebec Neuroblastoma Screening Project12 (Woods WG, manuscript submitted for publication) and the German Neuroblastoma Screening Project13 (Schilling FH, manuscript submitted for publication). Both were prospective, population-based cohort studies with appropriate geographic controls. After collectively screening almost 2 million children, both studies documented a marked increased incidence in the screened cohorts, whether screening was performed at 6 months or younger12 or at 14 months (Schilling FH, manuscript submitted for publication). The more mature North American study has documented no decrease in neuroblastoma mortality (Woods WG, manuscript submitted for publication), whereas the larger German study has shown no decrease in the incidence of advanced-stage disease, and hence very little likelihood that there will be a decrease in neuroblastoma mortality (Schilling FH, manuscript submitted for publication). There are lessons from these world-wide pediatric trials, some of which are directly applicable to adult cancer, especially prostate cancer, for which major controversy over screening efficacy continues.13 Millions of men are screened every year with digital rectal examinations and prostate-specific antigen analysis; and prostate cancer incidence has increased dramatically.14,15 Several prospective controlled cohort studies designed to answer the question of prostate screening efficacy are in progress.16-18 However, no definitive results have been forthcoming, and no results are expected before 2010. What are some of the lessons from pediatric trials in cancer? First, as eloquently pointed out in an earlier Journal of Clinical Oncology editorial,19 pediatric oncologists offer clinical trials to virtually every child diagnosed with cancer in North America. Sixty percent (yes, 60%) of children actually are enrolled onto National Cancer Institute–sponsored cancer clinical trials, compared with 2% in adults. The increase in childhood cancer survival through widespread clinical trials has led to a marked lowering of mortality over the last 30 years that far outpaces reductions in adult cancer mortality. Although there are many factors for the successes made in childhood cancer, clinical trial participation seems to have played a role. Pediatric oncologists in the West have a long-standing history of performing clinical trials before implementing unproven approaches, even in newborns. Hence, answering scientific questions prospectively, although more work at the onset, leads to much more straightforward results in the end. The Japanese continue to struggle to justify their neuroblastoma screening program, despite the fact that in the well-performed trials from elsewhere noted above, the evidence is overwhelming that screening for neuroblastoma is ineffective at reducing mortality (Woods et al, manuscript submitted for publication; Schilling et al, manuscript submitted for publication). Screening studies such as those in North America and Germany, while costing millions of dollars to perform over a 10- to 15-year period, have saved their respective healthcare systems tens of millions of dollars yearly. The cost-effectiveness of such well-controlled prospective studies cannot be overstated. Why, then, is there not more emphasis put on potential lack of cost-effectiveness in prostate cancer? How many billions of dollars have been spent on men in this country who are having prostate-specific antigen levels measured on a regular basis, with countless thousands evaluated and undergoing potentially unnecessary operations and other treatments with little evidence that such an approach will ultimately affect the death rate from this most common cancer in older males? Physicians who care for adults are urged to wait for results of well-designed, prospective, controlled-cohort studies to determine whether screening actually reduces mortality in prostate cancer before automatically implementing screening of their patients. Even if screening reduces mortality, will it be cost-effective? Internists and surgeons, take a lead from your pediatric colleagues: an ounce of prevention may not be worth a pound of cure. REFERENCES 1. Ries LAG, Smith MA, Gurney JG, et al: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. NIH Pub. No 99-4649. Bethesda, MD, National Cancer Institute, SEER Program, 1999
2.
Woods WG, Tuchman M: Neuroblastoma: The case for screening infants in North America. Pediatrics 79: 869-873, 1987 3. Castleberry RP: Biology and treatment of neuroblastoma. Pediatr Clin North Am 44: 919-937, 1997[CrossRef][Medline] 4. Sawada T, Nakata T, Takasugi N, et al: Mass screening for neuroblastoma in infants in Japan. Lancet 2: 271-273, 1984[Medline] 5. Nishi M, Miyake H, Takeda T, et al: Effects of the mass screening of neuroblastoma in Sapporo City. Cancer 60: 433-436, 1987[CrossRef][Medline] 6. Bessho F, Hashizume K, Nakajo T, et al: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 119: 237-241, 1991[CrossRef][Medline]
7.
Yamamoto K, Hayashi Y, Hanada R, et al: Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture. Japan. J Clin Oncol 13: 2033-2038, 1995 8. Kaneko Y, Kanda N, Maseki N, et al: Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high risk neuroblastomas: A chromosome and N-myc amplification study. J Clin Oncol 8: 2005-2013, 1990[Abstract] 9. Suita S, Tajiri T, Akazawa K, et al: Mass screening for neuroblastoma at 6 months of age: Difficult to justify. J Pediatr Surg 33: 1674-1678, 1998[CrossRef][Medline] 10. Bessho F: Effects of mass screening on age-specific incidence of neuroblastoma. Int J Cancer 67: 520-522, 1996[CrossRef][Medline]
11.
Yamamoto K, Ohta S, Ito E, et al: Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: Cohort study in seven prefectures in Japan. J Clin Oncol 20: 1209-1214, 2002 12. Woods WG, Tuchman M, Robison LL, et al: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348: 1682-1687, 1996[CrossRef][Medline] 13. Schilling FH, Spix C, Berthold F, et al: German neuroblastoma mass screening study at 12 months of age: Statistical aspects and preliminary results. Med Pediatr Oncol 31: 435-441, 1998[CrossRef] 14. Schroder FH: Prostate cancer, in Kramer BS, Gohagan JK, Prorok PC (eds): Cancer Screening: Theory and Practice. New York, NY, Marcel Dekker, Inc, 1999, pp 461-514 15. Boyle P, Maisonneuve P, Napalkov P: Geographical and temporal patterns of incidence and mortality from prostate cancer. Urology 46: 47-55, 1995 (suppl 3A)[CrossRef][Medline]
16.
Kramer BS, Brown ML, Prorok PC, et al: Prostate cancer screening: What we know and what we need to know. Ann Int Med 119: 914-923, 1993 17. Gohagan JK, Levin DL, Proprok PC, et al: The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control Clin Trials 21: 249S-406S, 2000 (suppl)[CrossRef] 18. The International Prostate Screening Trial Evaluation Group: Rationale for randomised trials of prostate cancer screening. Int J Cancer 35: 262-271, 1999 (review article)
19.
Simone J: The evolution of cancer care for children and adults. J Clin Oncol 16: 2904-2905, 1998
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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